Researchers at UCLA’s David Geffen School of Medicine have designed three novel antibodies of the IgE class targeting antigens CD138, CD38, and transferrin receptor 1 (TfR1/CD71): cancer antigens present in various hematopoietic and/or solid tumors. There are several advantages of IgE class antibodies compared to the commonly used IgG class in the clinic such as the high affinity of IgE for its Fc receptors, which results in more efficient arming of effector cells that would be able to penetrate the tumor without losing surface-bound antibodies, and the expression of these receptors on relevant effector cells such as mast cells, monocytes, macrophages, eosinophils, basophils, Langerhans cells, and dendritic cells. Additional advantages are the low serum levels of IgE that result in less competition with endogenous antibodies for Fc receptor occupancy and the fact that, in contrast to IgG, IgE does not have an inhibitory Fc receptor, which decreases the antibody effector functions.
BACKGROUND
Immunoglobulins (Ig’s), also known as antibodies, are glycoprotein molecules produced in plasma cells. Ig’s are crucial to immune response, explicitly recognizing and binding to particular antigens present on bacteria, viruses, or cancer cells. Various classes of Ig’s (e.g., IgG, IgA, IgE) differ in their structure and biological features. Due to the complex and exceedingly specific nature of Ig’s for antigens, they have been used to target various cancer cells. The IgG class of Ig’s has experienced the most significant development for cancer therapy but has only shown partial treatment efficacy in the clinic. More recently, the IgE class antibody has started to be considered for cancer therapy. In fact, the IgE antibodies targeting tumor antigens have already been developed and so far have shown efficacy and have been well-tolerated in preclinical models as well as in the clinic. There is a dire need to create new IgE constructs to target a more diverse population of tumor antigens. Importantly, antibodies of the IgE class can be used in combination with other drugs including IgG antibodies engaging different Fc receptors and/or effector cells and maximizing the anti-tumor activity. In fact, combination treatment of cancer with multiple drugs is part of the standard care.
INNOVATION
UCLA researchers have developed a series of new IgE antibodies for cancer therapy, explicitly targeting tumor antigens CD138 (syndecan-1), CD38, and TfR1 (CD71). These three targets are expressed in the incurable malignancy multiple myeloma (MM). However, each of these targets have distinct expression for other malignancies that could be targeted with this novel series of IgE antibodies. For instance, CD138 expression is present in non-Hodgkin lymphomas (NHL), prostate cancer, breast cancer (including triple negative breast cancer), colorectal cancer, and kidney cancer. While CD38 expression is present in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), aggressive natural killer (NK) cell leukemia (ANKL), NK/T-cell lymphoma, and NHL. The overlap of target expression for a number of these diseases is seen with TfR1 – known as the universal cancer marker – sharing distinct expression for ALL, NHL, and CLL. The developed antibodies thus propose a multifaceted approach to targeting a wide array of malignancies.
POTENTIAL APPLICATIONS
• Hematological cancers including: Non-Hodgkin lymphomas (NHL), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), aggressive natural killer (NK) cell leukemia (ANKL), NK/T-cell lymphoma, and multiple myeloma (MM).
• Epithelial cancers including lung, ovarian, prostate, breast (including triple negative), colorectal, and kidney cancers.
ADVANTAGES
• IgE class antibodies have high affinity for target Fc receptors
• Longer half-life on the surface of effector cells
• Less competition for Fc receptor occupancy
• Target antigens are present in a broad variety of tumors
• It could be a generalizable standard care therapy (both monotherapy and combination therapy)
DEVELOPMENT-TO-DATE: These novel IgE antibodies have already been developed and exhibit their expected properties.